CYP2C19 polymorphism has no correlation with the efficacy and safety of thalidomide in the treatment of immune-related bowel disease.

OBJECTIVE: To explore the relationship between hepatic cytochrome P450 2C19 (CYP2C19) gene polymorphisms and the effectiveness and safety of thalidomide in the treatment of patients with immune-related bowel disease (IRBD). METHODS: CYP2C19 variants in 79 patients treated with thalidomide were analyzed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The clinical response and adverse events of the thalidomide treatment were recorded. The potential influences of the CYP2C19 genotype polymorphisms on the clinical efficacy and adverse events of thalidomide were then investigated. RESULTS: Altogether 79 patients with IRBD (70 with Crohn's disease, three with ulcerative colitis and six with Behcet's disease) receiving thalidomide therapy were recruited from January 2013 to February 2015 in a tertiary IBD center in China. Overall, 21.5% (17/79) of these patients had CYP2C19 poor metabolizers genotype (PM). The overall response rate and the incidence of adverse events of CYP2C19 extensive metabolizers genotype were not significantly different from that of the PM when IRBD patients were treated with thalidomide (P = 0.517 and 0.816, respectively). CONCLUSION: CYP2C19 polymorphisms do not seem to be associated with efficacy of thalidomide and the incidence of adverse events in treating IRBD.

Analysis of genetic mutations associated with anti-malarial drug resistance in Plasmodium falciparum from the Democratic Republic of East Timor.

BACKGROUND: In response to chloroquine (CQ) resistance, the policy for the first-line treatment of uncomplicated malaria in the Democratic Republic of East Timor (DRET) was changed in early 2000. The combination of sulphadoxine-pyrimethamine (SP) was then introduced for the treatment of uncomplicated falciparum malaria. METHODS: Blood samples were collected in two different periods (2003-2004 and 2004-2005) from individuals attending hospitals or clinics in six districts of the DRET and checked for Plasmodium falciparum infection. 112 PCR-positive samples were inspected for genetic polymorphisms in the pfcrt, pfmdr1, pfdhfr and pfdhps genes. Different alleles were interrogated for potential associations that could be indicative of non-random linkage. RESULTS: Overall prevalence of mutations associated with resistance to CQ and SP was extremely high. The mutant form of Pfcrt (76T) was found to be fixed even after five years of alleged CQ removal. There was a significant increase in the prevalence of the pfdhps 437G mutation (X2 = 31.1; p = 0.001) from the first to second survey periods. A non-random association was observed between pfdhfr51/pfdhps437 (p = 0.001) and pfdhfr 59/pfdhps 437 (p = 0.013) alleles. CONCLUSION: Persistence of CQ-resistant mutants even after supposed drug withdrawal suggests one or all of the following: local P. falciparum may still be inadvertently exposed to the drug, that mutant parasites are being "imported" into the country, and/or reduced genetic diversity and low parasite transmission help maintain mutant haplotypes. The association between pfdhfr51/pfdhps437 and pfdhfr 59/pfdhps 437 alleles indicates that these are undergoing concomitant positive selection in the DRET.

Lack of tacrolimus circadian pharmacokinetics and CYP3A5 pharmacogenetics in the early and maintenance stages in Japanese renal transplant recipients.

AIMS: We investigated whether tacrolimus pharmacokinetics shows circadian variation and the influence of the CYP3A5 A6986G polymorphism on the pharmacokinetics in both the early and maintenance stages after renal transplantation. METHODS: Tacrolimus was administered twice daily at specified times (09.00 and 21.00 h) throughout the pre- and post-transplant period according to the trough-targeting strategy. Fifty recipients with stable graft function were studied on day 28 and beyond 1-year post transplantation. Whole blood samples were collected prior to and 1, 2, 3, 4, 6, 9 and 12 h after both the morning and evening doses during hospitalization. RESULTS: Tacrolimus pharmacokinetics did not show circadian variation in either the early or maintenance stage [AUC(0-12) 197.1 (95% confidence interval 182.9, 212.3) in daytime vs. 203.6 ng h ml(-1) (189.8, 217.4) in the night-time at day 28, 102.0 (92.1, 111.9) vs. 107.7 (97.9, 117.5) at 1 year, respectively]. In CYP3A5 *1 allele carriers (CYP3A5 expressers), body weight-adjusted oral clearance was markedly decreased from the early stage to the maintenance stage [0.622 (0.534, 0.709) to 0.369 l h(-1) kg(-1) (0.314, 0425)] compared with a smaller decrease [0.368 (0.305, 0.430) to 0.305 (0.217, 0.393)] in CYP3A5 non-expressers; however, the CYP3A5 genetic variation did not influence tacrolimus chronopharmacokinetics. CONCLUSION: Equivalent daytime and night-time tacrolimus pharmacokinetics were achieved during both the early and maintenance stages with our specified-time administration strategy. The CYP3A5 polymorphism may be associated with the time-dependent changes in the oral clearance of tacrolimus, suggesting that genotyping of this polymorphism is useful for determining the appropriate dose of tacrolimus in both the early and maintenance stages after renal transplantation.

Paraoxonase activity and genetic polymorphisms in northern Han Chinese workers exposed to organophosphate pesticides.

Paraoxonase (PON1) is one of the major players in the detoxification of organophosphates (OPs). This study presents our investigation into the effect of OPs on serum PON1 activity and the distribution of common PON1 polymorphisms in Han Chinese workers with repeated high exposure to OP pesticides, and the factors modulating PON1 activity. In all, 400 participants, including 180 workers exposed to OP pesticides occupationally, and 220 controls were investigated. Serum PON1 and cholinesterase (ChE) activity were measured, and genotyping was done using polymerase chain reaction-restriction fragment length polymorphism. The association between PON1 activity and PON1 polymorphisms, and the influencing factors of PON1 activity, were analyzed. The results revealed that repeated OP exposures significantly decreased serum PON1 and ChE activity (P< 0.05), although the exposed workers did not complain of health problems. Higher L and R allele frequencies for the L55M and Q192R polymorphisms of PON1 were observed. PON1 polymorphisms (especially the Q192R polymorphism) and pesticide exposures significantly affected serum PON1 activity in the study population. Therefore, the results of this investigation indicate PON1 polymorphisms and pesticide exposures may be important risk predictors for OP poisoning in the Han Chinese population, who display very high frequencies of the M allele and R allele for PON1 polymorphisms at the positions 55 and 192, respectively.

Impacts of different nanoparticles on functional bacterial community in activated sludge.

Rapidly developing industry raises concerns about the environmental impacts of nanoparticles, but the effects of inorganic nanoparticles on functional bacterial community in wastewater treatment remain unclear. The discriminated effects of silver nanoparticles (Ag-NP) and zinc oxide nanoparticles (ZnO-NP) in a simulated sequencing batch reactor (SBR) system were therefore evaluated by the RNA-based terminal restricted fragment length polymorphism (T-RFLP), 16S rcDNA gene clone library and real-time reverse transcription-PCR (RT-PCR) analyses. Although the COD and NH4-N removal efficiencies were not or slightly reduced by the addition of ZnO-NP and Ag-NP, the functional bacterial community changed remarkably. The denitrification related species were inhibited by high dosage of ZnO-NP and Ag-NP, including Diaphorobacter species, Thauera species and those in the Sphaerotilus-Leptothrix group. However, the bacteria related to sludge bulking, heavy metal resistant and biosorption were increased, especially by ZnO-NPs treatment, including those closely related to Haliscomenobacter hydrossis, Zoogloea ramigera and Methyloversatilis universalis. In addition, Ag-NP and ZnO-NP treatments influenced the functional bacterial community differently. Increasing of bulking related bacteria may help to compensate the COD removal efficiency and to maintain functional redundancy, but could lead to operation failure of activated sludge system when expose to ZnO-NPs.

Polymorphisms in the p53 pathway genes and micronucleus occurrence in Chinese vinyl chloride-exposed workers.

OBJECTIVES: To investigate the association between polymorphisms in the p53 pathway genes and chromosomal damage in vinyl chloride (VC)-exposed workers. MATERIALS AND METHODS: Cytokinesis block micronucleus test was performed in 310 VC-exposed workers and 149 non-exposed workers to determine chromosomal damage. The polymerase chain reaction and restriction fragment length polymorphism technique were used to detect six SNPs in the p53 pathway genes involved in the cell cycle. RESULTS: There was a highly significant dose-response relationship between VC exposure and chromosomal damage. Individuals carrying the variant genotypes were at higher risk for chromosomal damage compared with their wild type genotype: p53rs1042522, MDM2 Del1518rs3730485, MDM2rs2279744 and GADD45Ars532446. On the other hand, individuals possessing the variant genotype of CDKN2A rs3088440 had significantly decreased risk compared with the corresponding wild-type. CONCLUSIONS: Genetic polymorphisms in P53 pathway genes may have an impact on VC-induced chromosomal damage.